This invention relates generally to methods for repairing tissue using adhesive compositions comprised of a hydrophilic polymer and crosslinked biomaterials. More specifically, the invention relates to tissue repair using a composition of collagen and crosslinkable components.
Tissue damage can result from many causes. Examples of such causes include surgical incisions, such as internal and epidermal surgical incisions; prosthetic implants, including injury attendant surgery such as hip replacements; and wounds, including lacerations, incisions, and penetrations. Often such damage is the result of herniation wherein the outer layers of the abdominal wall weaken, tear, or bulge. The resulting weakened area or hole allows for sections of the inner lining of the abdominal cavity, or peritoneum, to protrude. This protrusion can be painful and if uncorrected can result in strangulation of the protruding tissue. Although almost all tissue can become herniated, the tissue in the inguinal canal, in the navel, and surrounding the location of former incisions are most common. Since the early 1980""s, the surgical techniques used in repairing inguinal or groin hernias have undergone a profound transformation. One such technique incorporates a surgically acceptable patch as part of the groin hernia repair. Goussous. (1995), xe2x80x9cEffectiveness Of The Mesh Plug Techniquexe2x80x9d (letter). Surgery; 117:600. Over time scar tissue forms around the reinforcing mesh, creating a supporting wall to minimize future hernias.
Various methods for approaching the herniated tissue and affixing the mesh prosthesis have been developed. There are two primary techniques used in hernia repair. In the traditional xe2x80x9copen surgeryxe2x80x9d technique, the surgeon makes a three- to four-inch incision in the abdominal wall, pushes the hernial sac inside and uses mesh to reinforce the abdominal wall. The other method of hernia repair is the laparoscopic technique, wherein three tiny incisions, about the size of dime, provide the surgeon sufficient access to reposition the hernia sac back through its hole and secure a mesh patch over the weak area in the muscle wall. The incisions used in the laparoscopic technique are sufficiently small so that they can be covered by adhesive strips and there is minimal or no scarring.
The surgically acceptable patch used in both of the above-discussed techniques is generally held in place via suturing or stapling to the surrounding tissue. Unfortunately, the use of such sutures or staples may increase the patient""s discomfort and increase the incidencesof wound infection, vascular injury and entrapment neuropathy. While herniorrhaphies have been conducted without firmly connecting the patch to the tissue surface and allowing the pressure of the peritoneum to hold the patch against the posterior side of the abdominal wall, see Zieren et al. (1999) xe2x80x9cIs Mesh Fixation Necessary In Abdominal Hernia Repair?xe2x80x9d Lang. Arch Surg. 384:71-75, fixation of the patch is generally preferred in order to avoid folding, shrinkage, and migration of the patch and is usually considered to be essential in laparoscopic procedures.
Recently cyanoacrylates and fibrin glues have been used as fixatives in hernia repair. While Katkhouda et al. (2001) Ann. Surg. 233:18-25 present the use of a fibrin sealant as a patch fixative, such fibrin products are made from human products and are thus susceptible to contamination. Also, fibrin adhesives are difficult to prepare and to store. The use of cyanoacrylates as adhesives also presents problems in that the adhesive may not be biocompatible and may not provide a sufficient degree of elasticity thereby resulting in increased patent discomfort and an increased incidence of reoccurrence. See, Farouk et al. (1996), xe2x80x9cPreliminary Experience with utyl-2-Cyanoacrylate adhesive in Tension-Free Inguinal Hernia Repair,xe2x80x9d Brit. J. Surg. 83:1100 and Jourdan et al. (1998), xe2x80x9cThe Use of N-Butyl-2-Cyanoacrylate Glue for the Fixation of Polypropylene Mesh in Laparoscopic Hernia Repair,xe2x80x9d 6th World Cong. of Endo. Surg., 1221-1225.
A new method of tissue repair has now been developed using a surgically acceptable hydrophilic-based crosslinking adhesive. The use of this adhesive composition avoids the potential complications inherent in suture or staple based methods of tissue attachment. Also, as the hydrophilic polymer-based adhesive does not contain human blood products, the danger of contamination present with fibrin adhesives is removed. While providing a stronger adhesive bond than fibrin adhesives such as TISSEEL(copyright), the hydrophilic polymer-based crosslinking adhesive is much more flexible than cyanoacrylate adhesives and is completely biocompatible.
U.S. Pat. No. 5,162,430, to Rhee et al., and commonly owned by the assignee of the present invention, discloses collagen-synthetic polymer conjugates prepared by covalently binding collagen to synthetic hydrophilic polymers such as various derivatives of polyethylene glycol.
Commonly owned U.S. Pat. No. 5,324,775, to Rhee et al., discloses various inert, naturally occurring, biocompatible polymers (such as polysaccharides) covalently bound to synthetic, hydrophilic polyethylene glycol polymers.
Commonly owned U.S. Pat. No. 5,328,955, to Rhee et al., discloses various activated forms of polyethylene glycol and various linkages which can be used to produce collagen-synthetic polymer conjugates having a range of physical and chemical properties.
Commonly owned, copending U.S. application Ser. No. 08/403,358, filed Mar. 14, 1995, a European counterpart of which was published as EP 96102366, discloses a crosslinked biomaterial composition that is prepared using a hydrophobic crosslinking agent, or a mixture of hydrophilic and hydrophobic crosslinking agents. Preferred hydrophobic crosslinking agents include any hydrophobic polymer that contains, or can be chemically derivatized to contain, two or more succinimidyl groups.
Commonly owned U.S. Pat. No. 5,580,923 to Yeung et al., discloses a composition useful in the prevention of surgical adhesions. The composition has a substrate, which is preferably collagen and a binding agent, which preferably has at least one tissue-reactive functional group and at least one substrate-reactive functional group.
Commonly owned U.S. Pat. No. 5,614,587 to Rhee et al., discloses bioadhesive compositions having collagen crosslinked using a multifunctionally activated synthetic hydrophilic polymer, as well as methods of using such compositions to effect adhesion between a first surface and a second surface. At least one of the first and second surfaces is preferably a native tissue surface.
Japanese patent publication No. 07090241 discloses a composition used for temporary adhesion of a lens material to a machining device, which contains a mixture of polyethylene glycol, having an average molecular weight in the range of 1000-5000, and poly-N-vinylpyrrolidone, having an average molecular weight in the range of 30,000-200,000.
West and Hubbell, Biomaterials (1995) 16:1153-1156, disclose the prevention of post-operative adhesions using a photopolymerized polyethylene glycol-co-lactic acid diacrylate hydrogel and a physically crosslinked polyethylene glycol-co-polypropylene glycol hydrogel, Poloxamer 407(copyright).
Each publication cited above and is incorporated herein by reference to describe and disclose the subject matter for which it is cited.
The invention is directed to a method of repairing tissue, such as herniated tissue, using a versatile biocompatible adhesive composition not previously disclosed or envisioned by those in the biomaterial field. The composition has a hydrophilic polymer and crosslinkable components that may be readily crosslinked upon admixture with an aqueous medium to provide a crosslinked composition suitable for use as a bioadhesive. The adhesive composition is biocompatible, and does not leave any toxic, inflammatory or immunogenic reaction products at the site of administration. Preferably, the composition is not subject to enzymatic cleavage by matrix metalloproteinases such as collagenase, and is therefore not readily degradable in vivo. As a result, the adhesive composition will degrade more slowly than either the hydrophilic polymer component or the crosslinkable component as the two components will serve to mutually protect each other from the effects of metalloproteases or hydrolysis.
Accordingly, in one aspect of the invention, a method for tissue repair is provided utilizing a readily crosslinkable, biocompatible, adhesive composition to secure a surgically acceptable patch to the damaged tissue. The adhesive composition is comprised of a hydrophilic polymer, a crosslinkable component A having m nucleophilic groups, wherein mxe2x89xa72; and a crosslinkable component B having n electrophilic groups capable of reaction with the m nucleophilic groups to form covalent bonds, wherein nxe2x89xa72 and m+n greater than 4. In the composition, each of components A and B is biocompatible and nonimmunogenic, at least one of components A and B is a hydrophilic polymer, and admixture of components A and B in an aqueous medium results in crosslinking of the composition to give a biocompatible, nonimmunogenic, crosslinked matrix.
Each of the crosslinkable components may be polymeric, in which case at least two crosslinkable components are generally although not necessarily composed of a purely synthetic polymer rather than a naturally occurring or semi-synthetic polymer, wherein xe2x80x9csemi-syntheticxe2x80x9d refers to a chemically modified naturally occurring polymer. Alternatively, one or two of crosslinkable components A and B may be a low molecular weight crosslinking agent, typically an agent comprised of a hydrocarbyl moiety containing 2 to 14 carbon atoms and at least two functional groups, i.e., nucleophilic or electrophilic groups, depending on the component. For convenience, the term xe2x80x9cpolynucleophilicxe2x80x9d will be used herein to refer to a compound having two or more nucleophilic moieties, and the term xe2x80x9cpolyelectrophilicxe2x80x9d will be used to refer to a compound having two or more electrophilic moieties. The adhesive composition may also additionally comprise an optional third biocompatible and nonimmunogenic crosslinkable component C having at least one functional group selected from (i) nucleophilic groups capable of reacting with the electrophilic groups of component B and (ii) electrophilic groups capable of reacting with the nucleophilic groups of component A.
Any conventional surgical procedure may be used to access the herniated tissue and any conventional surgically acceptable patch may be affixed with the adhesive composition. For example, a polypropylene patch may be affixed to the posterior surface of the abdominal wall via laparoscopic surgical techniques or may be affixed to the anterior surface via open surgical techniques. The method is applicable to a wide variety of hernia types, including but not limited to, inguinal hernias, femoral hernias, scrotal hernias, ventral hernias, umbilical hernias, ventral/epigastric hernias, incisional hernias, spigelian hernias, recurrent hernias, recurrent incisional hernias, bilateral hernias, stoma hernias, and hiatus hernias.
In another aspect of the invention, a kit is provided comprising the adhesive composition as discussed above and a surgically acceptable patch.
In a still further aspect of the invention, a pretreated patch is provided comprising a surgically acceptable patch that has been coated with the adhesive composition as discussed above.